Compelling evidence suggests that both genetic factors and environmental factors play important roles in the pathogenesis of PD. Over 13 genetic loci have been identified in the familial forms of PD. Aging and a number of neurotoxins, including MPTP and certain pesticides, are known risk factors of human parkinsonia. However, the underlying molecular mechanism of the disease-associated environmental factors, particularly, their interaction with genetic factors in PD pathogenesis, remains poorly understood. It is thought that epigenetic changes are mediators between genetic determinants and aging or environmental toxins. In a preliminary study, we determined the global methylation status of 80,000-110,000 highly informative CpG sites in brain tissue from a series of sporadic PD patient and well-matched control patients utilizing novel sequencing technique and we found that multiple genes involved in neurogenesis, particularly the ones in the wnt signaling pathway, were hypermethylated in PD brains. Consistent with this notion, genome-wide expression analysis of SH-SY5Y cells treated with sub-lethal dosage of MPP+ revealed reduced expression of genes in wnt pathways along with increased expression of cytokine genes. These findings demonstrate that specific functional pathways, such as the wnt pathway, are epigenetically dysregulated during the pathogenesis and progression of PD. Our preliminary results support an important role of epigenetic regulation in PD pathogenesis. Based on these exciting preliminary data, we hypothesize that environmental risk factors contribute significantly to initiation and progression of PD via, at least partially, an epigenetic- involved mechanism. In this study, we propose to determine the functional pathways dysregulated by DNA methylation in PD patient brains. We will also determine whether known environmental toxins induce similar changes of DNA methylation in mouse models. Finally, we will select the wnt pathway as a target to determine the role of its dysregulation in the pathogenesis of PD as proof of concept. Successful completion of the study will provide novel insights into the mechanisms through which environmental factors contribute to PD pathogenesis and identify genes or pathways as potential targets for future development of therapeutic reagents.